Serine hydroxymethyltransferase (SHMT) catalyzes the retro-aldol cleavage of serine to yield glycine and the hydroxymethyl group is transferred to 5,6,7,8-tetrahydrofolate to generate 5,10-methylene-H4-folate. It is a ubiquitous enzyme found in all prokaryotes and eukaryotes. This enzyme plays an important role in channeling metabolites between amino acid and nucleotide metabolism (reviewed in Rao et al., Int J Biochem Cell Biol 32: 405-416, 2000). Elevated SHMT1 activity has been shown to be coupled to the higher demand of DNA synthesis in rapidly proliferating cells, particularly tumor cells (Snell et al., Br J Cancer 57, 87-90, 1988).
SHMT along with thymidylate synthase and dihydrofolate reductase constitutes the thymidylate synthase cycle. Dihydrofolate reductase and thymidylate synthase have been favourite targets for the development of anticancer drugs. A common problem encountered in clinical situations using these inhibitors is the emergence of drug resistance. The currently known inhibitors of SHMT also proved to be not entirely satisfactory. For example, the classical inhibitors of DHFR, viz. methotrexate and its structural analogs including quinazolines, failed to inhibit SHMT activity significantly.
There is a need in the art for novel SHMT-modulating agents that are useful in cancer chemotherapy. The instant invention fulfills this and other needs.